Method of obtaining halogen products of diaminopyridine



' i No Drawing.

' Patented Na. 3,1931

UNITE f-S JS ia-Mm:"

EDMOND T. TIsz IiERNAItD does, or YONKERS, NEW YORK, ASSJGNORS TO THErYRInIUM CORPORATION, or vEPEnA "PARK, NEW YORK, "A"CORPORATION or VYORK .5

i This invention is an improvement in meth-' .odslof obtaining halogensubstitution products'of diaminorpyridine', and more part cuable formedicinal use. v r v One of the primary objects 'j'larly in a methodoflobtaining bromo diammoi-pyridine, substantially colorless and suitofthe inven ",'tion is the provisionof a methodof prepar- 'ing" fromalpha-alpha diamino-pyridine, a substantially colorless product suitablefor medicinal use, internallyor externally, in

' that it is relatively, nontoxic to the host, While capable ofrendering pathogenic micro-0rganisms innocuous? o It is known thatalpha-alpha-diaminopyridine is very toxic, and only slightly bacteriostatic, so'thatit cannot be used for me-,

dicin'al purposes. However, it has been demonstrated that the azocompounds of alphaalpha-diaminopyridine have ery distinct bactericidalproperties, and are relatively nontoxic. That is,while theyv act in themam ner desired on pathogenic 1nicro-organisms,-

Ethey are innocuous to the host. Similar results may be obtained byintroducing halogen into the 'diaminopyridme;

; Attempts to brominate alpha-alpha-dianr' inopyridinedirectlyfheretofore were not sat-' isfactory. However, abromo-alpha-alpha diamino pyridine; may be obtained by brominatingdiactyl-alpha-alpha-diamino-pyridine. i With this object inview,lbromine is reacted directly with a solutionofdiacetylalpha-alpha-diaminmpyridirie, in a suitable solvent, such asWater, or'the like, and therprimary product is saponified to obtain thebro-l mo-alpha alpha{liamiho-pyridirie. ex-

ample of the is'givenbelow.

- a flm m tj Diacetyl alpha alph diaminopyridine (M; P. 205) tothe'amountiof30 gms. is 'dis-' METHo-noroBrAmIife "HAVLOYGE'N rnonuc'rsor DIAMINOPYBIDINE,

solution is'cooled' to 85", and 5 cc. ferricchld ride solution of 10%are added as'a halogen carrienafterwhich 27' gms: (9 cc.); of 'bro mineare "added under constant stirring:

lWhen all ofthe bromine has been added, the color of the liquid isblack. l/Vater to'the amountof 500 cc.- is added to the liquid, which is,then boiled, andthe small quantity of the black precipitate is filteredoil. 1 The solution is then made slightly alkaline with concentratedsodium hydroxide solution and again boiled; The alkali changes ithecolorof the liquid to a lightibrownish y'ellow,'with ..a small rated. Theresulting" brown colored" substanceiswashed with cold water, to dissolvethe sodiumlbr omide, and unchanged diacetyl diaminopyridine, "tallizedout of toluol'or distilled waterwith the addition -to acons'tant meltingpoint. a The beta-bromo-alpha-compound crystallizes-out of water, inlong, thick, cream colcreani colored'needles. Its melting point uble in"cold water and in cold toluol. *T'llhe compound dissolves more easilyinhot 'w'a'ter,-*and i's'yery soluble in hottoluol. It

issoluble 'in 'al'cohfol, ether, chloroform, car-v bon tetrachloride,andyerysoluble in acetone.

and the residue is'recrys- .t

of asm'all quantity'of charcoal,

'ored needles, and out of toluol, short, thick,

174"to 1.75",(3. The compound is slightlysolsolved in 900 a. 'ofwater byboiling The l 'Thecompound is" soluble in dilute or concen trated'acids, Concentrated 7 sodium hydroxide solution will precipitate thecompound from the soluble in dilute alkalies.

It is our opinion that the b-romination i takes 'place'in the betaposition, but this statejmentis purely theoretical and not intended as alimitation, as the halogen may go partacid solution, though it issomewhat lull I f V ,3 iii-ii 11 ly into the gamma position. In theevent thatthe-bromination takes place in the beta position, as Webelieve, the end product would be inaccordance with the formula :1 I

v n HZN' N NHz y The ,ibromo-alpha-Ialpha-diaminopyridine 19 obtained asabove described, has a distinct bactericidal action against the commonpath ogenic germs, and its tox'icity is 'l'ssthan r that ofalpha-alpha-dian1in0 pyridine 'lhe- Y s r compound is intended fortherapeutic use,-

and to serve as a starting material-for the production of other newsubstances, :1 a Other members of the halogenvgroup, chlorine oriodine,1nay obviouslyused'in I v place-of bromineto obtain halogensubsti- I '20 tuted productso f alpha-a1pha dian1ino-pyridine. v r pwhatsisolaimed asnewrisz lrTheinethod of obtainingabetahalogen.substituted alpha-a-lphaf-diarnino-pyridine, which consists in reactingdiacetyl-alphaf alpha-dialnino-pyridine in solution with the halogen,andsaponifying the product V 2.Themethod.ofreducing the toxic-ity of alphaalpha-diamino-pyridine,' whicln'coiisistsin introducing a halogen intothe beta i position o-f th e pyridine ring -o1 the alphaalphadianiinoepyridine. "3. The method of obtaining abeta bromine substitutedalpha-alpha-dianiino-pyridine, which consists in treating: the diacetyl,pro dj uotofthesaidcompound aqueous solution g V s i l with thebromine; andconsequentlysaponip V. a a tying thep'rimary product; i ckfAs anew article of manufacture, a substa'ntiallyqcol orless medicinalsubstance composed vofialpha-alpha-diamindpyridine with ahalog'en in thebeta position of thelpyridine rin 7 Y u V 7.

- -5i As anewarticlejof manufacture, a beta- V :brorno compound ofalphaealpha-diamino- 1 pyridine substantially colorless, crystallizedfrom waterortolu'oh; j Signediat.Yonkers inthecounty of West- 1 rchester and State of New York this 2nd day ",of MayA.D.1929. L r H y 5EDMONDT; TISZA BERNARDJOOSL

